PROJECT SUMMARY/ABSTRACT Vascular cognitive impairment (VCI) due to cerebral small vessel disease (SVD) is now recognized as a key public health issue evidenced by the 2016 NIH Alzheimer's Disease-Related Dementias Summit recommendations. Although individual neuroimaging biomarkers such as cerebral microbleeds (MB) or white matter hyperintensities (WMH) are often used in the diagnosis and monitoring of VCI due to small vessel disease, no single neuroimaging biomarker has emerged as a valid surrogate marker for small vessel VCI trials. This may be because it remains uncertain if any single biomarker more strongly impacts cognition compared to the others or if there is a cumulative effect of these lesions. Recent emerging evidence strongly suggests that new diffusion tensor imaging (DTI) measures can reliably capture the cumulative effect of different SVD lesions in patients with various forms small vessel VCI. These DTI-based biomarkers are thus highly promising candidate biomarkers for VCI trials. The purpose of this proposal is to use the well- characterized small vessel disease cerebral amyloid angiopathy (CAA) to validate DTI as a SVD biomarker by determining 1) DTI's association with cognitive impairment independent of other imaging parameters, and 2) DTI's underlying biologic mechanism. CAA is an age-related SVD that is a common cause of small vessel VCI and is characterized by progressive deposition of ?-amyloid (A?) in the wall of cortical and leptomeningeal small arteries. Neuropathological evidence suggests that CAA contributes to dementia independent of other age-related neuropathologies, including Alzheimer's disease (AD). All of the individual biomarkers of small vessel VCI are seen in CAA, including MB and WMH. Additionally, autopsy studies suggest that cerebral microinfarctions (CMI), an important feature of small vessel VCI, are common in CAA. CAA is also associated with DTI changes that appear to correlate with clinically important measures like executive function and processing speed. CAA thus represents an ideal model of small vessel VCI. The current proposal first aims to show that DTI-based biomarkers strongly track cognitive change in CAA. Secondly, it aims to establish the histopathologic basis of these biomarkers in order to produce a biologically validated biomarker for use in clinical trials in CAA and small vessel VCI. Successful conclusion of the proposed aims has high potential for elucidating the mechanistic basis of DTI abnormalities in CAA and would result in a trial-ready DTI-based biomarker for potential candidate treatments in small vessel VCI. Insights gained from these studies will also be critical in defining the tissue injury mechanisms to be targeted when selecting future candidate treatments for small vessel VCI. The proposed analyses aim to build a complete bridge from neurologic function to in vivo DTI, ex vivo DTI, and ultimately to gold-standard neuropathology. While these studies involve CAA, we anticipate that this DTI-based biomarker would be broadly applicable to many types of small vessel VCI seen in the clinic.